Myostatin (GDF-8) is a new TGF-beta family member that is essential for proper regulation of skeletal muscle mass. We have shown that mice lacking myostatin have 2-3 times the amount of muscle present in wild type animals and that this increase in muscle mass results from a combination of hyperplasia and hypertrophy. We have also shown that overexpression of myostatin in nude mice induces a wasting syndrome that resembles the cachectic state often seen in human patients with chronic diseases such as cancer or AIDS. The overall aims of this proposal are to determine the role of the Smad signaling pathway in mediating the effects of myostatin in vivo, to investigate the role of the Smad pathway in regulating muscle growth, and to explore the possibility that inhibition of myostatin activity and/or Smad signaling may have applications in the treatment of cachexia. The specific aims of this proposal are: to generate and characterize transgenic mice in which the expression levels of myostatin can be manipulated; to generate and characterize transgenic mice in which a dominant negative form of myostatin or the pro- domain of myostatin is used to block myostatin expression and/or signaling; to generate and characterize transgenic mice in which either dominant negative forms or inhibitors of various TGF-beta signaling components are expressed specifically in skeletal muscle; to determine whether these signaling components are involved in myostatin signaling in mice; to determine whether the activities of these signaling components are essential for the wasting syndrome induced by IL-6, TNF-alpha, and certain tumor cells; and to determine the effects of blocking the activities of these signaling components postnatally in skeletal muscle. These studies will provide key information regarding the signaling molecules involved in the regulation of muscle growth and will be an important first step in investigating the possible benefits of targeting myostatin or the Smad pathway as a strategy for developing novel therapies for the treatment of cachexia.